| Abstract: | Oxidative damage and inflammation are both implicated in the genesis ofhypertension; however, the mechanisms by which these stimuli promotehypertension are not fully understood. Here, we have described a pathway inwhich hypertensive stimuli promote dendritic cell (DC) activation of T cells,ultimately leading to hypertension. Using multiple murine models ofhypertension, we determined that proteins oxidatively modified by highlyreactive γ-ketoaldehydes (isoketals) are formed in hypertension andaccumulate in DCs. Isoketal accumulation was associated with DC production ofIL-6, IL-1β, and IL-23 and an increase in costimulatory proteins CD80 andCD86. These activated DCs promoted T cell, particularly CD8+ T cell,proliferation; production of IFN-γ and IL-17A; and hypertension. Moreover,isoketal scavengers prevented these hypertension-associated events. PlasmaF2-isoprostanes, which are formed in concert with isoketals, were found to beelevated in humans with treated hypertension and were markedly elevated inpatients with resistant hypertension. Isoketal-modified proteins were alsomarkedly elevated in circulating monocytes and DCs from humans withhypertension. Our data reveal that hypertension activates DCs, in large part bypromoting the formation of isoketals, and suggest that reducing isoketals haspotential as a treatment strategy for this disease. |
